Method for preparing dihydrocodeinone, dihydromorphinone, and codeinone



' Patented Feb. 17, 1953 ,METHOD' FOR PREPARING 'DIH YDROCO DEINONE;DIHYDROMORPHINONE; AND

CODEINONE' August: H..Homeyer,' Webster Groves,:a nd- George B. DeLa Mater, St. Louis County, -Mo.,- assignors toMallinckrodt ChemicalWorks, St. Louis,.M.6., acorporation of Missouri Nd Drawing. -Application october 20, 19 49,

Serial-No. 122,586 l This :invention relates. :tothe .zproduction .:.of

narcotics. and more particularly. to a process for the manufacture of morphine derivatives.

This application is a continuation-in-part of our copending application:Serial No. 76,854, fi1ed February 16, 19495nowabandoned.

Briefly this invention provides an...effective method for the preparation of dihydro'codeinone from dihydrocodeine, of-codeinonefrom codeine, and "of 'dihydromorphinone from ..dihydromorphine by oxidation witha ketone in .the presence of an aluminum alkoxide.-

Among the objects of thi invention are the provision of an improved process forithe manufacture of morphine derivatives such as dihy- -drocodeinone, dihydromorphinone Land codeinoneythe provision of a processof thetypeset forth .which employs readily. available starting imaterials; provision of a process of? theutype re.-

ferred. to which'gives good yields of dihydrocode- 'inone, vdihydromorphinone or codeinone with.-

out' simultaneous formation of substantial amounts of accompanying by products; and .the provision of a process of the type. indicated which permits-the recovery of .unreacted start.- ing material ,from the .reaction .mixture- .Other objects will be in partapparent and..'in part pointed out. hereinafter.

The invention accordingly. comprises the. steps and sequence of steps, and: features .of imanipulation, which will. be: exemplified .in': theumethods .10 Claims.- v 01. 260-285) hereinafter describe'd,.-aand the; scope 1 of the; ap- I plication ofvv which will .be indicated. .in: the following claims.

Dihydrocodeinone 'is' a starting material in the .manufactureaof/the..valuablemew: analgesic .idrug metopomzaand is L itselL-an; analgesiciofe considerable value for-the. alleviation --of coughs, being more active than codeine in this respect. Until now; dihydrocodeinone has-been obtained principally by the.catalytic; hydrogenation of the naturally occurring opium alkaloid thebaine; but supplies of this natural alkaloid'are limited and asatisfactory and economical synthesis from a more readily obtainable starting material has .not been available.

Codeine on the other-handis readily available and can be converted to dihydrocodeine almost quantitatively. by catalytic hydrogenation, but the known methods for effecting the transformation of dihydrocodeineto dihydrocodeinone give very poor yields and the processes are-beset with so many difiiculties aslto beimpracticable.

Similar problems are encountered in the'production ,of. codeinone and dihydromorphinone. Although-these are valuablepharmaceuticals a satisfactory method for the production of code .inone from codeineand dihydromorphinonefrom .dihydromorphineliasnot been available.

We have discovered that if the oxidation of dihydrocodeine ,to dihydrocodeinone, of codeine .to codeinone andof dihydromorphine to dihydromorphinone is eifected by certain ketones in the presence of aluminum alkoxid'es,dihydrocodeine, .codeine and dihydromorphine can be converted respectively to dihydro'codeinone, codeinone'and dihydromorphinone in good yield. The unoxidized dihydrocodeine, codeine or dihydromorphine can be conveniently and substantially'completelyrecovered, thus making the over-all conversion virtually complete.

The reactions are represented by the-following equations; l

omenwhere R and mare-organic residues. 5

For this reaction, a ketone having a sufllciently high oxidation potential is necessary but the ketone must not contain other functional groups which will destroy or condense with dihydrocodeinone, dihydrocodeine, codeine, codeinone, dihydromorphinone or dihydromorphine. Quinone, for example, possesses a very high oxidation potential, but, when it was used as the oxidizing agent in these reactions, the product was a dark insoluble substance from which no oxidized product could be isolated. It has been found that ketones of the following general formula are valuable in the process of this invention:

Bri l- 2 where R1 is a radical selected from the group consisting of monocyclic hydrocarbon aryl and aralkyl derivatives and R2 is radical selected from the group consisting of alkyl radicals and monocyclic hydrocarbon aryl and aralkyl radicals, one of which contains a substituent selected from the group consisting of alkoxy radicals and carbonyl oxygen on the alpha-carbon atom. Examples of such ketones are benzil, benzoin methyl ether, and alpha-methoxyacetophenone. Mixtures of such ketones may likewise be employed.

While many aluminum alkoxides will serve in this reaction, it is preferred that the alkoxides be derived from alcohols which are not themselves oxidized under the conditions of this reaction. Such alkoxides are the aluminum tertiary-alkoxides.

If the aluminum alkoxi-de is not freshly prepared or if an excess of it is used, it has been found that the unreacted dihydrocodeine is transformed to its stereoisomer, dihydro-isoco- .deine, without affecting the quality or yield of the desired ketone. This does not aflect the over-all conversion to dihydrocodeinone, since the isomer is oxidized under the same conditions as dihydrocodeine itself. If dihydrocodeine is reacted with an aluminum alkoxide without the ketone, it is substantially converted to dihydrois-ocodeine. This is a simple and convenient method for preparing the latter compound which heretofore could be prepared only by involved and diflicult procedures. Dihydroisooodeine is an analgesic which, so far as is known, possesses properties generally quite similar to those of dihydrocodeine.

The reaction should be carried out in a suitable solvent. Any of the inert solvents, such as benzene, toluene or xylene, may be employed.

The following examples illustrat specific embodiments of this invention:

Example 1 -In a 500 ml. flask were placed anhydrous dihydrocodeine (10 g.; 0.033 mole), benzil (21 g.; 0.10 mole) and dry toluene (250 ml.). Solvent (50 ml.) was distilled from the reaction mixture and to the bright yellow solution was added aluminum tertiary-butoxide (1 g.; 0.0040 mole). A deep red color developed almost immediately and after the solution had been refluxed for 18 hours it had assumed a dark brown coloration.

The solution was cooled, shaken with Rochelle salt solution (50 ml.) and filter aid (5 g.), and filtered. The clear, brown organic layer was shaken with 2% hydrochloric acid solution (100 ml.). The aqueous and toluene layers became yellow incolor and a small quantity of a heavy dark brown oillseparated. The dark oil and 'aqueous phase were drawn off into a second separatory funnel and treated with two 20 ml. portions of chloroform, which dissolved the oil and permitted complete separation of the acid layer. The aqueous layer was treated with one gram of decolorizing carbon and filtered. The clear yellow filtrate was cooled and stirred mechanically and sodium hydroxide solution was added dropwise. When a permanent turbidity appeared, sodium hydrosulfite (0.1 g.) was added to prevent discoloration and a seed crystal of dihydrocodeinone was added. Deposition of crystalline product began and the addition of sodium hydroxide was continued until the solution was strongly alkaline to phenolphthalein. The dense, finely crystalline precipitate, which proved to be crude dihydrocodeinone, was filtered off, washed with water and dried. The yield of material melting at -190 C. was 3.63 g. (36%).

Example 2 In a 500 ml. flask were placed anhydrous dihydrocodeine (10 g.; 0.033 mole), the methyl ether of benzoin (45 g.; 0.2 mole) and dry toluene (250 ml.). Solvent (50 ml.) was distilled off and to the remaining solution was added aluminum tertiary-butoxide (4 g.; 0.016 mole). The solution assumed a red brown color almost at once, and was all-owed to reflux for one hour.

The cooled solution was shaken with Rochelle salt solution (50 ml.) and filter aid (5 g.), and was filtered. The light yellow organic layer was separated from the filtrate and extracted with a total of 100 ml. of 2% hydrochloric acid. The acid extract was shaken with one 25 ml. portion of chloroform and two 50 ml. portions of ether, diluted to 200 ml. with water and cooled in an ice bath with mechanical stirring. The solution was slowly neutralized with sodium hydroxide, and when the first oily precipitate appeared was seeded with dihydrocodeinone. Crystallization set in and the addition of sodium hydroxide was continued until the solution was strongly alkaline. The white crystalline precipitate was filtered off, washed with water and dried. The yield of dihydrocodeinone melting at -194 C. was 6.10 g.

Extraction of the alkaline mother liquor with chloroform and evaporation of this extract to dryness yielded an additional 3.20 grams of crude dihydrocodeinone mixed with dihydrocodeine.

Example 3 Following the procedure described in Example 1, anhydrous dihydrocodeine (10 g.; 0.033 mole), a-methoxy acetophenone (15 g.; 0.1 mole), aluminum tertiary-butoxoide (1 g.; 0.004 mole) and toluene (200 ml.) were refluxed for 16 hours. The yield of dihydrocodeinone was 3.0 g.

Example 4 Following the procedure described in Example 1, anhydrous dihydrocodeine (10 g.; 0.033 mole), benzil (21 g.; 0.1 mole), aluminum isopropoxide (0.6 g.; 0.003 mole) and toluene (200 ml.) were refluxed for 44 hours. The yield of crude dihydrocodeinone was 0.93 g.

Example 5 cooled mixture was shaken with diluted hydrochloric acid (5 ml. concentrated acid and 70 ml. water) and the acid extract was washed with two successive --inl. portions of chloroform followed by two successive 25-1111. portions of ether. A solution of potassium sodium tartrate (20 ml.) was added to the acid extract; the resulting solution was heated to expel ether and then made alkaline with ammonium hydroxide. When the sides of the container were scratched, a crystalline precipitate formed. 'This precipitate of crude dihydroinorpninone was filtered off and dried, then dissolved in hot 9Q% alcoho1 (90 ml.) and an excess of oxalic acid was added. After the solution had cooled and the sides or the container had been scratched, a crystalline acid oxalate salt formed. This was filtered off and recrystallized from 90% alcohol. The purified salt was dissolved in water and converted to the free base with ammonium hydroxide. The purified dihydromorphinone weighed 1.? g. It was compared with an authentic sample of dihydromorphinone and the two were found to be identical.

Example 6 The reaction described in the preceding example was repeated using g. of benzil in place of benzoin methyl ether. The reaction mixture was refluxed for seventeen hours and pure dihydromorphinone was again recovered.

Many variations and modifications of this invention will be apparent to those skilled in the art. For example, the particular aluminum tertiary-alkoxide employed is not critical, aluminum tertiary-butoxide lceine' preferred because of its availability.

In View of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

We claim:

1. The process for preparing a substance selected from the group consisting of dihydrocodeinone, dihydrcinorphinone and codeinone which comprises reacting the corresponding hydroxy compound selected from the group consisting of dihydrocodeine, dihydroisocodeine, codeine and dihydromorphine in the presence of an aluminum tertiary-allroxide and a solvent, with a ketone having the general formula in which R1 is a radical selected from the group consisting of monocyclic hydrocarbon aryl and aralkyl radicals, and R2 is a radical selected from the group consisting of allryl radicals and monocyclic hydrocarbon aryl and arallryl radicals, one of said radicals containing a substituent in the alpha position selected from the group consisting of alizoxy radicals and carbonyl oxygen.

2. The process for preparing dihydrocodeinone which comprises reacting dihydrocodeine with benzil in the presence of an aluminum tertiaryalkoxide and a solvent.

3. The process for preparing dihydrocodeinone which comprises reacting dihydrocodeine with benzoin methyl ether in the presence of an aluminum tertiary-alkoxideand a solvent.

4. The process for preparing dihydrocodeinone which comprises reacting dihydrocodeine with a-methoxyacetophenonc in the presence of an aluminum tertiary-alkoxide and a solvent.

5. The method of preparing dihydrocodeinone which comprises reacting dihydrocodeine with henzil in the presence of aluminum tertiarybutoxide and toluene.

6. The method of preparing dihydrocodeinone which comprises reacting dihydrocodeine with benzoin methyl ether inthe presence of aluminum tertiary-butoxide and toluene.

'7. The process for preparing dihydromorphinone which comprises reacting dihydromorphine with benzil in the presence of an aluminum tertiary-alkoxide and a solvent.

8. The process for preparing dihydromorphinone which comprises reacting dihydromorphine with benzil in the presence of aluminum tertiary-hutoxide and toluene.

9. The method of preparing dihydrocodeinone which comprises reacting dihydrocodeine with a-methoxyacetophenone in the presence of aluminum tertiary-butoxide and toluene.

10. The process for preparing dihydrocodeinone which comprises reacting dihydroiscodeine in the presence of an aluminum tertiary-alkoxide and a solvent, with a ketone having the general formula in which R1 is a radical selected from the group consisting of monocyclic hydrocarbon aryl and. aralkyl radicals, and R2 is a radical selected from the group consisting of alkyl radicals and monocyclic hydrocarbon aryl and aralkyl radicals, one of said radicals containing a substituent in the alpha position selected from the group consisting of alkoxy radicals and carbonyl oxygen.

AUGUST H. HOMEYER.

GEORGE E. DE LA MATER.

REFERENQES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,379,832 Serini et a1. July 3, 1945 2,384,335 Oppenauer Sept. 4, 1945 FOREIGN PATENTS Number Country Date 415,097 Germany June 13, 1925 OTHER REFERENCES Baker et al., J. Am. Chem. Soc, vol. 65, pp. 1675-1676 (1943). 

1. THE PROCESS FOR PREPARING A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF DIHYDROCODEINONE, DIHYDROMORPHINONE AND CODEINONE WHICH COMPRISES REACTING HE CORRESPONDING HYDROXY COMPOUND SELECTED FROM THE GROUP CONSISTING OF DIHYDROCODEINE, DIHYDROIZOCODEINE, CODEINE AND DKHYDROMORPHINE IN THE PRESENCE OF AN ALUMINUM TERTIARY-ALKOXIDE AND A SOLVENT, WITH A KETONE HAVING THE GENERAL FORMULA 